rs138442805

Variant names:

• chr20-8740457-C-T
• rs138442805
• NM_015192.4:c.2413+9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015192.4(PLCB1):​c.2413+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,471,662 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (11 hom., cov: 32)
  • Exomes 𝑓: 0.013 (130 hom.)
• Consequence: PLCB1 NM_015192.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.582
• Publications: 1 publications found

Genes affected

PLCB1 (HGNC:15917): (phospholipase C beta 1) The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals. This gene is activated by two G-protein alpha subunits, alpha-q and alpha-11. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PLCB1 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 12

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-8740457-C-T is Benign according to our data. Variant chr20-8740457-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00899 (1369/152270) while in subpopulation NFE AF = 0.016 (1091/68026). AF 95% confidence interval is 0.0152. There are 11 homozygotes in GnomAd4. There are 604 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015192.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB1	NM_015192.4	MANE Select	c.2413+9C>T		intron	N/A	NP_056007.1	Q9NQ66-1
	PLCB1	NM_182734.3		c.2413+9C>T		intron	N/A	NP_877398.1	Q9NQ66-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB1	ENST00000338037.11	TSL:1 MANE Select	c.2413+9C>T		intron	N/A	ENSP00000338185.6	Q9NQ66-1
	PLCB1	ENST00000378637.6	TSL:1	c.2413+9C>T		intron	N/A	ENSP00000367904.2	Q9NQ66-2
	PLCB1	ENST00000378641.7	TSL:1	c.2413+9C>T		intron	N/A	ENSP00000367908.3	Q9NQ66-2

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1370 AN: 152152 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00920 AC: 1937 AN: 210542 AF XY: 0.00912

Gnomad AFR exome AF: 0.00261

Gnomad AMR exome AF: 0.00285

Gnomad ASJ exome AF: 0.00896

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.0133 AC: 17530 AN: 1319392 Hom.: 130 Cov.: 19 AF XY: 0.0129 AC XY: 8507 AN XY: 661020

African (AFR) AF: 0.00197 AC: 57 AN: 28862

American (AMR) AF: 0.00387 AC: 126 AN: 32598

Ashkenazi Jewish (ASJ) AF: 0.00873 AC: 209 AN: 23932

East Asian (EAS) AF: 0.00 AC: 0 AN: 37674

South Asian (SAS) AF: 0.00107 AC: 80 AN: 74798

European-Finnish (FIN) AF: 0.00496 AC: 259 AN: 52220

Middle Eastern (MID) AF: 0.00202 AC: 11 AN: 5448

European-Non Finnish (NFE) AF: 0.0160 AC: 16091 AN: 1008448

Other (OTH) AF: 0.0126 AC: 697 AN: 55412

GnomAD4 genome AF: 0.00899 AC: 1369 AN: 152270 Hom.: 11 Cov.: 32 AF XY: 0.00811 AC XY: 604 AN XY: 74454

African (AFR) AF: 0.00217 AC: 90 AN: 41542

American (AMR) AF: 0.00595 AC: 91 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1091 AN: 68026

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0134 Hom.: 12

Bravo AF: 0.00942

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Developmental and epileptic encephalopathy, 12 (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.63
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138442805; hg19: chr20-8721104;